Employing the candidate genetic approach, we previously identified mutations in the gene encoding NEMO (NF- kB essential modulator), an intracellular signaling constituent of the NF-kB pathway, results in ectodermal dysplasia with an immune deficiency. Mutations in the zinc finger domain of NEMO block CD40 mediated activation of NF- kB and prevent B cells from undergoing class switch recombination (CSR) and APCs from synthesizing NF -kB regulated cytokines such as IL -12 or TNF-a when stimulated with CD40 ligand. The zinc finger domain of NEMO is a site for the covalent attachment of ubiquitin and this step is necessary for the full activation of NF-kappa B. The majority of patients with ectodermal dysplasia with immune deficiency have mutations in the zinc finger domain and we have found that such mutations impair the post- translational modification of NEMO by ubiquitin. Related efforts in the laboratory include making genetically altered mice with targeted mutations in signaling molecules, which regulate NF-kappaB. CYLD is a deubiquitinating enzyme that targets signaling constituents of the NF-kB signaling pathway, including NEMO. Alteration in CYLD have been described in patients with familial cylindromatosis, a condition characterized by numerous benign adnexal tumors. In mice deficient deficient in CYLD we previously showed that the development of B cells, T cells, and myeloid cells is unaffected in CYLD deficient mice, but that the activation of these cells with mediators of innate and adaptive immunity results in enhanced NF-kB activity and is associated with increased NEMO ubiquitination. CYLD deficient mice are more susceptible to induced colonic inflammation and show a dramatic increase in the incidence of tumors in a colitis associated cancer (CAC) model. These results suggest that CYLD limits inflammation and tumorigenesis by regulating NEMO ubiquitination in vivo. We are now studying the regulatory role of CYLD in other signaling pathways and are making a CYLD knockout NEMO knockin mice.

Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2010
Total Cost
$731,126
Indirect Cost
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State
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Wang, Hong-Ying; Ma, Chi A; Zhao, Yongge et al. (2013) Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK. Proc Natl Acad Sci U S A 110:5127-32
Temmerman, Stephane T; Ma, Chi A; Zhao, Yongge et al. (2012) Defective nuclear IKKýý function in patients with ectodermal dysplasia with immune deficiency. J Clin Invest 122:315-26
Fan, Xiying; Upadhyaya, Bhaskar; Wu, Liming et al. (2012) CD40 agonist antibody mediated improvement of chronic Cryptosporidium infection in patients with X-linked hyper IgM syndrome. Clin Immunol 143:152-61
Wu, Liming; Ma, Chi A; Zhao, Yongge et al. (2011) Aurora B interacts with NIR-p53, leading to p53 phosphorylation in its DNA-binding domain and subsequent functional suppression. J Biol Chem 286:2236-44
Ma, Chi A; Wang, Hong-Ying; Temmerman, Stephane et al. (2011) Dendritic cells from humans with hypomorphic mutations in IKBKG/NEMO have impaired mitogen-activated protein kinase activity. Hum Mutat 32:318-24
Wu, Liming; Ma, Chi A; Jain, Ashish (2011) When Aurora B met p53: newly revealed regulatory phosphorylation in an old protein. Cell Cycle 10:171-2
Wang, Hong-Ying; Jain, Ashish (2011) Novel sequencing-based strategies for high-throughput discovery of genetic mutations underlying inherited antibody deficiency disorders. Curr Allergy Asthma Rep 11:352-60
Murray, Patrick R; Jain, Ashish; Uzel, Gulbu et al. (2010) Pyoderma gangrenosum-like ulcer in a patient with X-linked agammaglobulinemia: identification of Helicobacter bilis by mass spectrometry analysis. Arch Dermatol 146:523-6
Wang, Hong-Ying; Gopalan, Vivek; Aksentijevich, Ivona et al. (2010) A custom 148 gene-based resequencing chip and the SNP explorer software: new tools to study antibody deficiency. Hum Mutat 31:1080-8
Lopez-Granados, Eduardo; Keenan, Jeffrey E; Kinney, Matthew C et al. (2008) A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency. Hum Mutat 29:861-8